Nitric oxide-generating silicone as a blood-contacting biomaterial.

Coagulation upon blood-contacting biomaterials remains a problem for short- and long-term clinical applications. This study examined the ability of copper(II)-doped silicone surfaces to generate nitric oxide (NO) and locally inhibit coagulation. Silicone was doped with 3-μm copper [Cu(0)] particles yielding 3 to 10 weight percent (wt%) Cu in 70-μm thick Cu/silicone polymeric matrix composites (Cu/Si PMCs). At 3, 5, 8, and 10 wt% Cu doping, the surface expression of Cu was 12.1% ± 2.8%, 19.7% ± 5.4%, 29.0% ± 3.8%, and 33.8% ± 6.5%, respectively. After oxidizing Cu(0) to Cu(II) by spontaneous corrosion, NO flux, J(NO) (mol · cm(-2) · min(-1)), as measured by chemiluminescence, increased with surface Cu expression according to the relationship J(NO) = (1.63%SA(Cu) - 0.81) × 10(-11), R(2) = 0.98, where %SA(Cu) is the percentage of surface occupied by Cu. NO flux at 10 wt% Cu was 5.35 ± 0.74 × 10(-10) mol · cm(-2) · min(-1). The clotting time of sheep blood exposed to these surfaces was 80 ± 13 seconds with pure silicone and 339 ± 44 seconds when 10 wt% Cu(II) was added. Scanning electron microscopies (SEMs) of coatings showed clots occurred away from exposed Cu dendrites. In conclusion, Cu/Si PMCs inhibit coagulation in a dose-dependent fashion related to the extent of copper exposure on the coated surface.</p

The Role of Porous Media in Modeling Fluid Flow Within Hollow Fiber Membranes of the Total Artificial Lung

<p>A numerical study was conducted to analyze fluid flow within hollow fiber membranes of the artificial lungs. The hollow fiber bundle was approximated using a porous media model. In addition, the transport equations were solved using the finite-element formulation based on the Galerkin method of weighted residuals. Comparisons with previously published work on the basis of special cases were performed and found to be in excellent agreement. A Newtonian viscous fluid model for the blood was used. Different flow models for porous media, such as the Brinkman-extended Darcy model, Darcy's law model, and the generalized flow model, were considered. Results were obtained in terms of streamlines, velocity vectors, and pressure distribution for various Reynolds numbers and Darcy numbers. The results from this investigation showed that the pressure drop across the artificial lung device increased with an increase in the Reynolds number. In addition, the pressure drop was found to increase significantly for small Darcy numbers.</p

Cardiac output during high afterload artificial lung attachment.

Attachment of thoracic artificial lungs (TALs) can increase right ventricular (RV) afterload and decrease cardiac output (CO) under certain conditions. However, there is no established means of predicting the extent of RV dysfunction. The zeroth harmonic impedance modulus, Z0, was thus examined to determine its effectiveness at predicting CO during high afterload TAL attachment. The MC3 Biolung was attached in four adult sheep groups based on baseline (BL) pulmonary vascular resistance and TAL attachment mode: normal, parallel (n=7); normal, series (n=7); chronic pulmonary hypertension, parallel (n=5), and chronic pulmonary hypertension, series (n=5). The resistance of each attachment mode was increased incrementally and instantaneous pulmonary system hemodynamic data were acquired at each increment. The change in Z0 from BL, DeltaZ0, and percent change in CO (DeltaCO%) were then calculated to determine their relationship. The DeltaCO% varied significantly with DeltaZ0 (p</p

The relationship between pulmonary system impedance and right ventricular function in normal sheep.

Right ventricular (RV) afterload is a key determinant of RV function and is increased in many cardiopulmonary pathologies. Pulmonary circulation input impedance has been used to quantify afterload previously but due to its complexity has not been widely applied. This study examines the effect of a subset of the impedance spectrum, the zeroth and first harmonic impedance moduli (Z (0), Z (1)), on RV performance in large animals. An artificial circuit with adjustable resistance and compliance (C) was implanted into the pulmonary circulation of five sheep. Resistance was varied to increase Z (0) in increments of 2 mmHg/(L/min) until Z (0) was 8 mmHg/(L/min) above baseline. At each Z (0), C was adjusted between 0, 0.5 and 2 mL/mmHg or 0, 1, and 5 mL/mmHg. Fourier transforms of the pulmonary artery pressure and flow in each situation were used to calculate the pulmonary impedance. Results show that the percent change in cardiac output (ÞltaCO) is linearly related to the change in Z (0) (DeltaZ (0)). Increases in Z (1) (DeltaZ (1)) decreased ÞltaCO but to a much smaller degree, with the effect of DeltaZ (1) increasing with DeltaZ (0). Regression of these results produce the equation: ÞltaCO = (-0.0829DeltaZ (1) - 3.65)DeltaZ (0) - 9.02 (R (2) = 0.69). Blood flow and pressure moduli are small at harmonics higher than the first and are unlikely to affect RV function. Therefore, during acute, high afterload states, Z (0) is the primary determinant of CO, while the effect of Z (1) is minor.</p

In-parallel attachment of a low-resistance compliant thoracic artificial lung under rest and simulated exercise.

<p>BACKGROUND: Previous thoracic artificial lungs (TALs) had blood flow impedance greater than that of the natural lungs, which could cause abnormal pulmonary hemodynamics. New compliant TALs (cTALs), however, have an impedance lower than that of the natural lung.</p> <p>METHODS: In this study, a cTAL of new design was attached between the pulmonary artery (PA) and the left atrium (LA) in 5 sheep (60.2 ± 1.9 kg). A distal PA band was placed to control the percentage of cardiac output (CO) routed to the cTAL. Rest and exercise conditions were simulated using a continuous dobutamine infusion of 0 and 5 μg/kg/min, respectively. At each dose, a hemodynamic data set was acquired at baseline (no flow to the cTAL), and 60%, 75%, and 90% of CO was shunted to the cTAL.</p> <p>RESULTS: Device resistance did not vary with blood flow rate, averaging 0.51 ± 0.03 mm Hg/(L/min). Under all conditions, CO was not significantly different from baseline. Pulmonary system impedance increased above baseline only with 5 μg/kg/min of dobutamine and 90% of CO diverted to the cTAL.</p> <p>CONCLUSIONS: Results indicated minimal changes in pulmonary hemodynamics during PA-LA cTAL attachment for high device flows under rest and exercise conditions.</p

Thoracic artificial lung impedance studies using computational fluid dynamics and in vitro models.

Current thoracic artificial lungs (TALs) possess blood flow impedances greater than the natural lungs, resulting in abnormal pulmonary hemodynamics when implanted. This study sought to reduce TAL impedance using computational fluid dynamics (CFD). CFD was performed on TAL models with inlet and outlet expansion and contraction angles, θ, of 15°, 45°, and 90°. Pulsatile blood flow was simulated for flow rates of 2-6 L/min, heart rates of 80 and 100 beats/min, and inlet pulsatilities of 3.75 and 2. Pressure and flow data were used to calculate the zeroth and first harmonic impedance moduli, Z(0) and Z(1), respectively. The 45° and 90° models were also tested in vitro under similar conditions. CFD results indicate Z(0) increases as stroke volume and θ increase. At 4 L/min, 100 beats/min, and a pulsatility of 3.75, Z(0) was 0.47, 0.61, and 0.79 mmHg/(L/min) for the 15°, 45°, and 90° devices, respectively. Velocity band and vector plots also indicate better flow patterns in the 45° device. At the same conditions, in vitro Z (0) were 0.69 ± 0.13 and 0.79 ± 0.10 mmHg/(L/min), respectively, for the 45° and 90° models. These Z(0) are 65% smaller than previous TAL designs. In vitro, Z(1) increased with flow rate but was small and unlikely to significantly affect hemodynamics. The optimal design for flow patterns and low impedance was the 45° model.</p

Performance of a MedArray silicone hollow fiber oxygenator.

A silicone hollow fiber oxygenator was evaluated to characterize gas transfer and biocompatibility. The device's fiber bundle was composed of MedArray's silicone hollow fibers with a 320 microm outside diameter, a 50 microm wall thickness, a surface area of 0.45 m, and a 0.49 void fraction. An in vitro gas exchange study was performed comparing the MedArray device (n = 9) with the Medtronic 0600 oxygenator (n = 6) using Association for the Advancement of Medical Instrumentation standards and blood flow rates of 0.5-1.75 L/min, and an oxygen to blood flow ratio of two. Biocompatibility and resistance studies were performed in vivo using a swine venovenous extracorporeal membrane oxygenation model (MedArray n = 5, Medtronic n = 5). Average O(2) transfer at 1 L/min was 86 ml/min/m in the MedArray device and 101.1 ml/min/m in the Medtronic device. At 0.5 L/min the MedArray and Medtronic device average resistance was 15.5 and 148.5 mm Hg/(L/min), respectively. Both devices had similar platelet consumption and hemolysis. Results indicate that the MedArray device has lower O(2) transfer efficiency, similar biocompatibility, and lower resistance than the Medtronic 0600 oxygenator. Optimization of the MedArray fiber bundle and housing design is necessary to improve O(2) transfer efficiency while maintaining lower device resistance than the Medtronic oxygenator.</p

Extracorporeal membrane oxygenation with subclavian artery cannulation in awake patients with pulmonary hypertension.

<p>Pulmonary hypertension (PH) is a challenging disease process to manage. Respiratory and hemodynamic changes that accompany general anesthesia lead to a significant risk of cardiovascular collapse. Certain cases of decompensated PH require extracorporeal membrane oxygenation (ECMO) support as either a bridge to lung transplantation or bridge to recovery. Performing ECMO cannulation without intubation or general anesthesia in these patients may be safer given the severity of their underlying disease process. We present three cases of upper body ECMO cannulation performed on patients with pulmonary hypertension while awake and without mechanical ventilation.</p

Use of a low-resistance compliant thoracic artificial lung in the pulmonary artery to pulmonary artery configuration.

<p>BACKGROUND: Thoracic artificial lungs have been proposed as a bridge to transplant in patients with end-stage lung disease. Systemic embolic complications can occur after thoracic artificial lung attachment in the pulmonary artery to left atrium configuration. Therefore, we evaluated the function of a compliant thoracic artificial lung attached via the proximal pulmonary artery to distal main pulmonary artery configuration.</p> <p>METHODS: The compliant thoracic artificial lung was attached to 5 sheep (63 ± 0.9 kg) in the proximal pulmonary artery to distal main pulmonary artery configuration. Device function and animal hemodynamics were assessed at baseline and with approximately 60%, 75%, and 90% of cardiac output diverted to the compliant thoracic artificial lung. At each condition, dobutamine (0 and 5 μg·kg(-1)·min(-1)) was used to simulate rest and exercise conditions.</p> <p>RESULTS: At rest, cardiac output decreased from 6.20 ± 0.53 L/min at baseline to 5.40 ± 0.43, 4.66 ± 0.31, and 4.05 ± 0.27 L/min with 60%, 75%, and 90% of cardiac output to the compliant thoracic artificial lung, respectively (P < .01 for each flow diversion vs baseline). During exercise, cardiac output decreased from 7.85 ± 0.70 L/min at baseline to 7.46 ± 0.55, 6.93 ± 0.51, and 5.96 ± 0.44 L/min (P = .82, P = .19, and P < .01 with respect to baseline) with 60%, 75%, and 90% of cardiac output to the compliant thoracic artificial lung, respectively. The artificial lung resistance averaged 0.46 ± 0.02 and did not vary significantly with blood flow rate.</p> <p>CONCLUSIONS: Use of a compliant thoracic artificial lung may be feasible in the proximal pulmonary artery to distal main pulmonary artery setting if its blood flow is held at less than 75% of cardiac output. To ensure a decrease in cardiac output of less than 10%, a blood flow rate less than 60% of cardiac output is advised.</p

A low mortality model of chronic pulmonary hypertension in sheep.

<p>BACKGROUND: Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep.</p> <p>METHODS: The vena cavae of nine sheep weighing 62 ± 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) every day for 60 d. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on d 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S).</p> <p>RESULTS: All sheep survived to 60 d. The average pulmonary artery pressure rose from 17 ± 1 mmHg at baseline to 35 ± 3 mmHg on d 56 with no significant change in cardiac output (8.7 ± 0.7 to 9.8 ± 0.7 L/min, P = 0.89). The RV:LV+S was significantly higher (0.42 ± 0.01, P < 0.001) than a historic group of untreated normal animals (0.35 ± 0.01, n = 13).</p> <p>CONCLUSION: This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy.</p